RU2462234C2 - Methods of stabilisation of oxidatively unsatable compositions - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions relate to field of medicine, in particular, to ophthalmology. Method of stabilisation of eye composition, which includes oxidatively unstable pharmaceutical ingredient is ensured by addition of efficient quantity of stabilising substance, where stabilising substance is selected from group, which consists of silicon dioxide, N,N,N',N',N",N"-hexa(2-pyridyl)-1,3,5- tris(aminomethyl)benzene, diethylenetriaminepentaacetic acid and salts of diethylenetriaminepentaacetic acid. Eye composition has pH from approximately 6.6 to approximately 7.2.

EFFECT: group of inventions ensures efficiency and stability of eye composition at higher temperatures.

32 cl, 2 tbl, 3 dwg, 3 ex

Description

FIELD OF TECHNOLOGY

The present invention relates to compositions of oxidatively unstable ophthalmic ingredients and methods for preparing such compositions.

RELATED APPLICATION

This application claims the priority of U.S. Patent Application No. 60/783557, “Methods for Stabilizing Oxidatively Unstable Pharmaceutical Compositions”, filed March 17, 2006.

BACKGROUND OF THE INVENTION

Therapeutic agents for topical administration to the eye are usually prepared in liquid or gel form, and they must remain sterile until administration. Accordingly, ophthalmic therapeutic agents are aseptically packaged, which is associated with significant difficulties and high cost, or sterilized by high temperature. Unfortunately, many therapeutic agents are not resistant to oxidation, especially at elevated temperatures.

EDTA (EDTA), Dequest (dekvest) and Desferal (desferal) were used to increase the stability of certain therapeutic agents in the process of autoclaving. However, there remains a need for other compounds capable of stabilizing unstable therapeutic agents that are susceptible to oxidative degradation. This need is satisfied by the present invention.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1. Stability study with ketotifen and PAA or EDTA.

Figure 2. Stability study with ketotifen and PAA or EDTA.

Figure 3. Stability study with ketotifen and PAA or DTPA.

DETAILED DESCRIPTION OF THE INVENTION

The present invention includes a method for stabilizing an ophthalmic composition comprising an oxidatively unstable pharmaceutical component, characterized in that said method comprises adding an effective amount of a stabilizing agent to the ophthalmic composition.

As used herein, the term “oxidatively unstable pharmaceutical ingredient” refers to pharmaceutical compounds or food additives used to treat eye conditions, such a compound degrading in the presence of oxygen and certain transition metals. Examples of pharmaceutical compounds include antihistamines, antibiotics, antibacterial agents, antiviral agents, antifungal agents, analgesics, anesthetics, antiallergic agents, mast cell stabilizers, steroidal and non-steroidal anti-inflammatory drugs, angiogenesis inhibitors; antimetabolites, fibrinolytics, neuroprotective drugs, angiostatic steroids, mydriatic agents, cyclopegic mydriatic agents, myotic agents, vasoconstrictor drugs, vasodilating agents, anti-coagulation agents, anticancer drugs, antisense drugs, immunomodulatory agents, angiogen inhibitor inhibitors, antigens VEGF antagonists, immunosuppressive drugs, and the like. In particular, examples of pharmaceuticals include (but are not limited to): acrivastine, antazoline, astemizole, azatadine, azelastine, buclizine, bupivacaine, cetirizine, clemastine, cyclizine, cyproheptadine, ebastine, emedastine, ephedrine, eucatropine, fexofinoten, hydroxyfenetine, hydroxyfenetine, hydroxyfenotene, levocabastine, levoceterizine, lomefloxacin, meclizine, mepivacaine, mechitazine, methdilazine, metapyrilene, mianserin, naphazoline, norastemizole, norebastine, ofloxacin, oxymetazoline, pheniramine, phenylephrine, physostigamine, terpamine, picuma, picuma n, tetrahydosoline, thiethylperazine, timolol, trimeprazine, triprolidine, their pharmaceutically acceptable salts and mixtures. Preferred pharmaceutical compounds include: acrivatine, antazolin, astemizole, azatadine, azelastine, clemastine, cyproheptadine, ebastine, emedastine, eukatropin, fexofenadine, gomatropin, hydroxyzine, ketotif, levocabastine, levoceterezinmethisinazolezinazolezinazolezinazolezinazolezinazolezinazolezinazolezinazolezinazolezinazolezinazolezinazolezinazolezinizolezinizolezinizolezinizolezinizolezinizolezina , physootigmine, picumast, promethazine, scopolamine, terfenadine, tetragyrozoline, fimilol, trimeprazine, triprolidine and their pharmaceutically acceptable salts. Particularly preferred pharmaceutical compositions include fenarimine, ketotifen, ketotifen fumarate, nor ketotifen, olapatadine and mixtures thereof. In particular, preferred pharmaceutical compositions include ketotifen, pharmaceutically acceptable salts and mixtures thereof.

Examples of nutritional supplements include vitamins and supplements such as vitamins A, D, E, lutein, zeaxanthin, lipoic acid, flavonoids, ophthalmologically compatible fatty acids such as omega 3 and omega 6 fatty acids, combinations thereof, combinations with pharmaceutical compounds, and t .P. Preferred pharmaceutical compounds or food additives are substances that degrade upon mixing these compounds and oxidation catalysts (such as metals and metal salts) at ambient temperature or elevated temperatures, in contrast to solutions of these compounds without oxidation catalysts at ambient temperature or elevated temperatures. Particularly preferred pharmaceutical compounds or food additives are substances that degrade by more than about 10% when heated to about 120ºC for about 20 minutes with oxidation catalysts. The concentration of oxidatively unstable pharmaceutical ingredients in the ophthalmic compositions of the invention is from about 2 μg / ml to about 0.5 g / ml, particularly preferably from about 0.1 μg / ml to about 10,000 μg / ml.

The term “ophthalmic composition” refers to liquids, aerosols or gels that can be administered topically into the eye. The term “stabilizing agent” refers to chelating compositions that inhibit metal-catalyzed oxidative degradation of an oxidatively unstable pharmaceutical ingredient. Examples of stabilizing agents include, but are not limited to, silicon dioxide, a chitin derivative such as chitosan, polyamides such as poly- (aspartic acid-co-ω-amino acid) ( See CAN: 129: 54671, Shibata, Minako et al. Graduate School Environmental Earth Science, Hokkaido University, Sapporo, Japan Macromolecular Symposia (1998), 130, 229-244) and polymeric amides such as poly- [iminocarbonyl (2,5-dihydroxy-1,4-phenylene) carbonylimino-1,4 -phenylenemethylene-1,4-phenylene], CAS # 87912-00-3, polymer lactams such as polyvinylpyrrolidone, polyamino carboxylic acids such as diethylene triamine pentaacetic acid and triethyl entriaminepentaacetic acid, polymeric amines such as polyallylamine, crown ethers such as 18-crown-6, 21-crown-7 and 24-crown-8, cellulose and its derivatives, N, N, N ', N', N ”, N” -hexa (2-pyridyl) -1,3,5-tris (aminomethyl) benzene and some macrocyclic ligands, such as crown ethers, ligand-containing units and chains ( See, David A. Leigh et al Angew. Chem Int. Ed., 2001 , 40 , No. 8, pgs. 1538-1542 and Jean-Claude Chambron et al. Pure & Appl. Chem. 1990 , Vol. 62, No. 6, pgs. 1027-1034). Preferred stabilizing agents are polyamino carboxylic acids, such as diethylenetriaminepentaacetic acid and triethylenetriaminepentaacetic acid. Particularly preferred stabilizing agents are diethylene triamine pentaacetic acid ("DTPA") or DTPA salts such as CaNa ₃ DTPA, ZnNa ₃ DTPA and Ca ₂ DTPA. The term "effective amount" means the amount of stabilizing agent necessary to inhibit the oxidative degradation of a pharmaceutical ingredient. In most cases, it is preferable that the molar ratio of the metal present in the ophthalmic composition to the chelate is 1: 1, more preferably about 1 part of the metal to more than about 1 part of the chelate compositions, most preferably about 1 part of the metal to more than or equal to approximately 2 parts of the chelate compositions. Regarding the concentration limits, it is preferred that the stabilizing agents have a concentration in the ophthalmic composition of from about 2.5 μmol / L to about 5000 μmol / L, more preferably from about 20 μmol / L to about 1000 μmol / L, more preferably from about 100 μmol / L to about 1000 μmol / L, most preferably from about 100 μmol / L to about 500 μmol / L.

In addition to the oxidatively unstable pharmaceutical ingredient and stabilizing agent, the ophthalmic composition contains carriers suitable for use in ophthalmology. Suitable carriers include antioxidants (radical scavengers), irritants, antibacterials, solubilizers, surfactants, buffers, tonicity agents, chelating agents, preservatives, wetting agents, thickeners, water, saline, mineral oil, petrolatum, petrolatum, water soluble solvents, such as C _15-20 alcohols, C _15-20 amides, C _15-20 alcohols substituted with zwitterions, vegetable oils or mineral oils, comprising from 0.5 to 5 wt.% hydroxyethyl cellulose, ethyl oleate, carboxymethyl cellulose, polyvinyl pyrrolidone and other non-toxic water-soluble polymers for use in ophthalmology, such as, for example, cellulose derivatives, such as methyl cellulose, alkali metal salts, carboxymethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, chitroxy cellulose, and hydroxyethyl cellulose, salts of poly- (acrylic acid) or ethyl acrylate, polyacrylamides, natural products such as gelatin, alginates, pectins, tragac ant, caramel gum, xanthan gum, carrageenin, agar and acacia, starch derivatives such as starch acetate and hydroxypropyl starch, as well as other synthetic products such as poloxamers, for example Poloxamer F127, polyvinyl alcohol, polyvinylpyrrolidone, polyvinyl ether, polyvinyl preferably crosslinked poly- (acrylic acid), such as neutral Carbopol or mixtures of these polymers. Preferred carriers are: water, cellulose derivatives such as methyl cellulose, alkali metal salts of carboxymethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, methyl hydroxypropyl cellulose and hydroxypropyl cellulose, neutral Carbopol or mixtures thereof. The concentration of the carrier is, for example, from 0.1 to 100,000 times the concentration of active ingredients, and the like. If the ophthalmic composition is eye drops, preferred carriers include water, pH buffered saline, mixtures thereof, and the like. A preferred carrier is an aqueous saline solution containing salts, including (without limitation) sodium chloride, sodium borate, sodium phosphate, sodium hydrogen phosphate, sodium divodoride phosphate, or the corresponding potassium salts. These ingredients are usually combined to form buffered solutions that include the acid and its conjugate base, so that the addition of acids and bases causes a relatively small change in pH. Buffer solutions may additionally include 2- (N-morpholino) ethanesulfonic acid (MES), sodium hydroxide, 2,2-bis (hydroxymethyl) -2,2 ', 2 ”nitrilotriethanol, n-tris (hydroxymethyl) methyl-2-aminoethanesulfonic acid , citric acid, sodium citrate, sodium carbonate, sodium bicarbonate, acetic acid, sodium acetate, ethylenediamine tetraacetic acid and the like. and their combinations. Most preferably, the carrier is buffered borate or phosphate buffered saline.

The invention further includes an ophthalmic composition comprising an oxidatively unstable pharmaceutical component and an effective amount of a stabilizing agent. The terms oxidatively unstable pharmaceutical ingredient, effective amount and stabilizing agents have the above meanings and preferred ranges.

Additionally, the invention includes a method for stabilizing an ophthalmic composition comprising an oxidatively unstable excipient, characterized in that said method comprises adding an effective amount of a stabilizing agent to the ophthalmic composition.

As used herein, the term “oxidatively unstable excipient” refers to a component of the ophthalmic compositions that deteriorate in the presence of oxygen and certain transition metals. Examples of unstable fillers include, but are not limited to, astringents, irritating agents, emollients, osmotic pressure increasing agents, oily agents, tonicity regulators, flour mimetics, and the like. In particular, examples of unstable fillers include (without limitation): cellulose derivatives, carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hyaluronic acid, methyl cellulose, Dextran, gelatin, polyols, glycerol, polyethylene glycol, polysorbate, propylene glycol oil, polypropylene glycol, , petrolatum, white ointment, white petrolatum, white wax and yellow wax. The terms “stabilizing agent” and “effective amount” have the above meanings and preferred ranges.

In addition, the invention includes an ophthalmic composition comprising an oxidatively unstable excipient and an effective amount of a stabilizing agent. The terms "oxidatively unstable filler", "stabilizing agent" and "effective amount" have the above meanings and preferred ranges.

Additionally, the invention includes a method for stabilizing an ophthalmic composition comprising an oxidatively unstable pharmaceutical ingredient, characterized in that the method includes:

(a) functionalizing said stabilizing agent with a polymerizable group,

(b) polymerizing an effective amount of the product of step (a) with at least one type of polymerizable monomer; and

(c) combining an ophthalmic composition comprising an oxidatively unstable pharmaceutical ingredient with the polymer of step (b).

The terms oxidatively unstable pharmaceutical ingredient, effective amount and stabilizing agents have the above meanings and preferred ranges. The term "functionalization" means a chemical compound of a polymerizable group with said stabilizing agent. Examples of the polymerizable group include (without limitation): methacrylate, acrylate, acrylamide and styrene. The term "polymerizable monomer" includes compounds containing olefinic moieties capable of being added to radical species such as propylene, ethylene and the like. The polymerization product of step (b) may be soluble or insoluble in the ophthalmic composition. Preferably, the polymerization product of step (b) is insoluble in the ophthalmic composition, and the polymerization product of step (b) can be in any form, such as rods, discs, containers, films, and the like.

In addition, the invention includes a method for stabilizing an ophthalmic composition comprising an oxidatively unstable excipient, characterized in that the method includes:

(a) functionalizing said stabilizing agent with a polymerizable group,

(b) polymerizing an effective amount of the product of step (a) with at least one type of polymerizable monomer; and

(c) combining an ophthalmic composition comprising an oxidatively unstable excipient with the polymer of step (b).

The terms “oxidatively unstable filler”, “effective amount”, “stabilizing agents”, “polymerizable group” and “polymerizable monomers” have the above meanings and preferred ranges.

In addition, the invention includes a container for an ophthalmic composition comprising an oxidatively unstable pharmaceutical ingredient, characterized in that said container comprises a polymerization product of an effective amount of a stabilizing agent functionalized by the polymerized group and at least one type of polymerizable monomer. The terms “oxidatively unstable pharmaceutical ingredient”, “effective amount”, “stabilizing agents”, “polymerizable group” and “polymerizable monomers” have the above meanings and preferred ranges.

In addition, the invention includes a container for an ophthalmic composition comprising an oxidatively unstable excipient, characterized in that said container comprises a polymerization product of an effective amount of a stabilizing agent functionalized by the polymerized group and at least one type of polymerizable monomer. The terms “oxidatively unstable filler”, “effective amount”, “stabilizing agents”, “polymerizable group” and “polymerizable monomers” have the above meanings and preferred ranges.

The advantages of the compositions and methods of this invention are numerous. First, ketotifen is known as an oxidatively unstable pharmaceutical ingredient. Known compositions containing ketotifen fumarate. These compositions contain EDTA, and their pH is approximately 5.5. These EDTA solutions stabilize ketotifen fumarate by preventing oxidative degradation, the pH of these solutions is below the threshold of sensation of the eye, so it is likely that the patient using this solution will feel discomfort due to the low pH of the solution. See Tang, I., Wong, DM, Yee, DJ and Harris, MG 1996. The pH of multi-purpose soft contact lens solutions. Optom. Vis Sci. 73: 746-749. Adler, FH 1959. Physiology of the Eye. Third edition. p.40. Brawner, LW and Jessop, DG 1962. A review of contact lens solutions. Contacto 6: 49-51. It was found that the stabilizing agents of the invention reduce the degradation of ketotifen fumarate at higher pH values than the pH of ketotifen fumarate solutions containing EDTA. The pH of the ophthalmic compositions of the invention is preferably from about 6.6 to about 7.2, more preferably from about 6.8 to about 7.0.

Secondly, it was shown that the shelf life of ketotifen fumarate solutions containing DTPA exceeds the shelf life of ketotifen fumarate solutions containing either EDTA or PAA. Thirdly, it is known that heating accelerates the degradation of many pharmaceutical ingredients. It has been shown that the stabilizing agents of the present invention are useful for reducing degradation associated with a higher temperature, such as sterilization temperature.

The following examples are provided to illustrate the invention. These examples do not limit the invention. They are intended only to offer a method for practicing the invention. Specialists in the field of contact lenses and other areas will determine other ways of carrying out the invention. However, these methods are also within the scope of this invention.

EXAMPLES

The following abbreviations apply:

PAA

Polyacrylic acid, a sodium salt having an average molecular weight of 200,000.

EDTA

Ethylenediamine tetraacetic acid.

Solution A

Deionized water containing the following ingredients by weight: NaCl (0.83%), boric acid (0.91%), sodium tetraborate decahydrate (0.1%).

Initial testing to determine the suitability of the ingredients

Excessive amounts of certain transition metals and their salts are known to lead to the degradation of ketotifen fumarate. The amount of metals and salts contained in commercially available ingredients is different, therefore, test batches of solution A were evaluated as follows. 200 g of solution A was stirred at ambient temperature, ketotifen fumarate (5 mg + 2 mg) was added and mixed until uniform. Six glass vials were filled with 3 ml of this solution. The vials were sealed with polytetrafluoroethylene ("PTFE") and the three vials were heated for eighteen minutes at 124 ° C. Samples of each treated vial (1.0-1.5 ml) were analyzed by HPLC and compared with untreated controls. If the amount of ketotifen in the treated vesicles decreased by five or less percent ( < 5%), the ingredients were determined as suitable for further studies and large batches of solution A were prepared from these ingredients.

Example 1

Obtaining solutions of ketotifen fumarate in PAA, EDTA

PAA (2000 μg / ml) was added to solution A, and 50 μg / ml ketotifen fumarate (approximately 36 μg / ml ketotifen) was dissolved in the system. EDTA (100 μg / ml) was added to another batch of solution A and 50 μg / ml ketotifen fumarate was dissolved in the system. Contact lenses with etafilcon A with a force of minus one and minus twelve (-1.0 and -12.0) diopters were placed in vials containing 3 ml of each of the above solutions. The vials were sealed with PTFE-coated rubber stoppers, sterilized at 124 ° C for 18 minutes and stored at ambient temperature for one year. Samples were taken over the course of the year and analyzed for the presence of ketotifen using HPLC. The results are shown in FIG. 1 and 2. These results show that there is a significant degradation of ketotifen in PAA and EDTA over time.

Example 2

Obtaining solutions of ketotifen fumarate in PAA, DTPA

To separate batches of solution A, Ca ₂ DTPA (100 μg / ml and 300 μg / ml, 213 and 640 μmol / L, respectively) and 2000 μg / ml (0.2%, approximately 18.51 mmol / L methacrylate) were added PAA and approximately 25 μg / ml ketotifen fumarate (approximately 18 μg / ml ketotifen) was dissolved in each of the systems. Samples of three ml of each solution were added to individual vials containing contact lenses. Each set of vials was sealed with PTFE plugs, sterilized at 124 ^° C for 18 minutes, and stored at 80 ^° C for two weeks. Samples were collected at various intervals and analyzed for the presence of ketotifen by HPLC. The results are shown in FIG. 3. These results show that there is a significant degradation of ketotifen over time with PAA, but not with the calcium salt of DTPA.

Example 3

Ketotifen fumarate solutions with oxidation catalysts

Ketotifen fumarate (50 μg / ml, approximately 36 μg / ml ketotifen) was dissolved in solution A containing approximately 500 μg / ml DTPA (approximately 1272 μmol / L DTPA) or sodium EDTA (Na ₂ C ₁₀ H ₁₄ O ₈ N ₂ · 2 H ₂ O, 1344 μmol / L EDTA). Approximately 50 μg / ml of the salts listed in Table 1 were dissolved in each of the solutions, and approximately 3 ml of each solution was dosed into several vials. The vials were sealed with PTFE-coated rubber stoppers and subjected to zero, one, two or three sterilization cycles as indicated in Table 1. One sterilization cycle is eighteen minutes of heating at 124 ° C. Samples were analyzed by HPLC for the concentration of ketotifen at the intervals shown in Table 2. These data show that, in the presence of oxidation catalysts, DTPA reduces oxidative degradation compared to EDTA.

Table 1 [salt] (mcg / ml) Metal salt Solution 16 MnSO ₄ .H ₂ O Manganese Solutions eighteen KMnO ₄ 16 MnOAc ₃ 25 FeSO ₄ .7H ₂ O Iron solutions 25 Fe ₂ O ₁₂ S ₃ .nH ₂ O 25 NiSO ₄ .7H ₂ O Nickel Solutions 25 NiF ₆ K ₂ 25 CuSO ₄ Copper solutions 26 Cu ₂ O

table 2 DTPA Stabilized Systems EDTA stabilized systems The number of cycles Fe Cu Ni Mn Fe Cu Ni Mn 0 36.29 36.35 36.40 35.57 36.15 35.78 36.34 33.54 one 35.14 36.13 36.48 34.33 19.41 35.33 34.46 23.98 2 34.10 36.19 36.10 33.71 12.84 34.89 32.75 18.01 3 33.28 35.92 36.22 33.34 7.73 34.71 29.91 12.89

Claims (32)

1. A method of stabilizing an ophthalmic composition comprising an oxidatively unstable pharmaceutical ingredient, characterized in that said method comprises adding an effective amount of a stabilizing agent to the ophthalmic composition, wherein the stabilizing agent is selected from the group consisting of silica, N, N, N ′, N ′ , N ″, N ″ - hexa (2-pyridyl) -1,3,5-tris (aminomethyl) benzene, diethylene triamine pentaacetic acid and diethylene triamine pentaacetic acid salts. 2. The method according to claim 1, characterized in that the stabilizing agent is selected from the group consisting of diethylene triamine pentaacetic acid and salts of diethylene triamine pentaacetic acid. 3. The method according to claim 1, characterized in that the effective amount of a stabilizing agent is from about 2.5 μmol / L to about 5000 μmol / L. 4. The method according to claim 1, characterized in that the effective amount of a stabilizing agent is from about 20 μmol / L to about 1000 μmol / L. 5. The method according to claim 1, characterized in that the effective amount of a stabilizing agent is from about 100 μmol / L to about 600 μmol / L. 6. The method according to claim 1, characterized in that the stabilizing agent is diethylene triamine pentaacetic acid. 7. The method according to claim 1, characterized in that the stabilizing agent is diethylene triamine pentaacetic acid or its salts, and an effective amount of said stabilizing agent is from about 100 μmol / L to about 1000 μmol / L. 8. The method according to claim 1, characterized in that the oxidatively unstable pharmaceutical ingredient is selected from the group consisting of: acrivastin, antazolin, astemizole, azatadine, azelastine, buclizine, bupivacaine, cetirizine, clemastine, cyclizine, cyproheptadine, ebastine, emedastine, eukuk, eukastatin, euk fexofenadine, gomatropin, hydroxyzine, ketotifen, levocabastine, levoceterizine, lomefloxacin, meclizine, mepivacaine, mechitazine, methdilazine, metapyrilene, mianserin, norastemizole, norebastine, ofloxacin, oxymethazazine, fizimenizin, promyshen, fizimenazin, promisen, fizimenazin lamin, terfenadine, tetragidozolin, thiethylperazine, timolol, trimeprazine, triprolidine, and pharmaceutically acceptable salts and mixtures thereof. 9. The method according to claim 1, characterized in that the oxidatively unstable pharmaceutical ingredient is selected from the group consisting of: acrivatine, antazoline, astemizole, azatadine, azelastine, clemastine, cyproheptadine, ebastine, emedastine, eucatropine, fexofenadine, gomatropin, hydroxyphene, k levocabastine, levoceterizine, meclizine, mechitazine, methdialazine, metapyrene, norastemizole, norebastine, oxymethazoline, fizootigmine, picumast, promethazine, scopolamine, terfenadine, tetragyrozolin, pharmimol, trimeprazine and triprolin, and triprol salt. 10. The method according to claim 1, characterized in that the oxidatively unstable pharmaceutical ingredient is selected from the group consisting of: phenarimine, ketotifen, ketotifen fumarate, ketotifen nor olopadadine fumarate, and mixtures thereof. 11. The method according to claim 1, characterized in that the oxidatively unstable pharmaceutical ingredient is selected from the group consisting of ketotifen, its pharmaceutically acceptable salts and mixtures thereof. 12. The method according to claim 1, characterized in that the oxidatively unstable pharmaceutical ingredient is selected from the group consisting of vitamins A, D, E, lutein, zeaxanthin, lipoic acid, flavonoids, ophthalmologically compatible fatty acids such as omega 3 and omega 6 fatty acids and their combinations. 13. The method according to claim 1, characterized in that the stabilizing agent is diethylene triamine pentaacetic acid or its salts, and an effective amount of said stabilizing agent is from about 100 μmol / L to about 1000 μmol / L, and the oxidatively unstable pharmaceutical ingredient is selected from the group consisting of ketotifen, its pharmaceutically acceptable salts and mixtures thereof. 14. The method according to claim 1, characterized in that the stabilizing agent is a calcium salt of diethylene triamine pentaacetic acid, an effective amount of said stabilizing agent is from about 100 μmol / L to about 1000 μmol / L, and the oxidatively unstable pharmaceutical ingredient is selected from the group consisting of ketotifen, pharmaceutically acceptable salts of ketotifen and mixtures thereof. 15. The method according to claim 1, characterized in that the ophthalmic composition has a pH from about 6.6 to about 7.2. 16. The method according to claim 1, characterized in that the ophthalmic composition has a pH from about 6.8 to about 7.2. 17. An ophthalmic composition comprising an oxidatively unstable pharmaceutical ingredient and an effective amount of a stabilizing agent, wherein the stabilizing agent is selected from the group consisting of silicon dioxide, a chitin derivative such as chitosan, cellulose, its derivatives, N, N, N ′, N ′, N '', N '' - hexa (2-pyridyl) -1,3,5-tris (aminomethyl) benzene, diethylene triamine pentaacetic acid, salts of diethylene triamine pentaacetic acid and acid. 18. An ophthalmic composition according to claim 17, characterized in that the stabilizing agent is selected from the group consisting of diethylene triamine pentaacetic acid and salts of diethylene triamine pentaacetic acid. 19. The ophthalmic composition according to claim 17, wherein the effective amount of the stabilizing agent is from about 2.5 μmol / L to about 5000 μmol / L. 20. An ophthalmic composition according to claim 17, wherein the effective amount of the stabilizing agent is from about 100 μmol / L to about 1000 μmol / L. 21. The ophthalmic composition according to claim 17, wherein the effective amount of the stabilizing agent is from about 100 μmol / L to about 600 μmol / L. 22. An ophthalmic composition according to claim 17, wherein the stabilizing agent is diethylene triamine pentaacetic acid. 23. The ophthalmic composition according to claim 17, wherein the stabilizing agent is diethylene triamine pentaacetic acid or its salts, and an effective amount of said stabilizing agent is from about 100 μmol / L to about 1000 μmol / L. 24. The ophthalmic composition according to claim 17, wherein the oxidatively unstable pharmaceutical ingredient is selected from the group consisting of: acrivastine, antazoline, astemizole, azatadine, azelastine, buclizine, bupivacaine, cetirizine, clemastine, cyclizine, cyproheptadine, ebastine, emedastine, emedastine, emedastine , fexofenadine, homatropine, hydroxyzine, ketotifen, levocabastine, levotseterizin, lomefloxacin, meclizine, mepivacaine, mehitazin, methdilazine, methapyrilene, mianserin, norastemizole, norebastin, ofloxacin, oxymetazoline, pheniramine, physostigmine, pikumast, about metazine, scopolamine, terfenadine, tetrahydozoline, thiethylperazine, timolol, trimeprazine, triprolidine, their pharmaceutically acceptable salts and mixtures. 25. The ophthalmic composition according to claim 17, wherein the oxidatively unstable pharmaceutical ingredient is selected from the group consisting of: acrivatine, antazoline, astemizole, azatadine, azelastine, clemastine, cyproheptadine, ebastine, emedastine, eucatropine, fexofenadine, homatropin, hydroxide , levocabastine, levoceterizine, meclizine, mechitazine, metapyrene, norastemizole, norebastine, oxymethazoline, physootigmine, picumast, promethazine, scopolamine, terfenadine, tetragyrozoline, fimilol, trimeprazine, and triprolidine are acceptable salt. 26. An ophthalmic composition according to claim 17, wherein the oxidatively unstable pharmaceutical ingredient is selected from the group consisting of: phenarimine, ketotifen, ketotifen fumarate, nor ketotifen fumarate, olopatadine, and mixtures thereof. 27. An ophthalmic composition according to claim 17, characterized in that the oxidatively unstable pharmaceutical ingredient is selected from the group consisting of ketotifen, its pharmaceutically acceptable salts and mixtures thereof. 28. The ophthalmic composition according to claim 17, wherein the oxidatively unstable pharmaceutical ingredient is selected from the group consisting of vitamins A, D, E, lutein, zeaxanthin, lipoic acid, flavonoids, ophthalmologically compatible fatty acids such as omega 3 and omega 6 fatty acids and their combinations. 29. The ophthalmic composition according to claim 17, wherein the stabilizing agent is diethylene triamine pentaacetic acid or its salts, and an effective amount of said stabilizing agent is from about 200 μmol / L to about 1000 μmol / L, and the oxidatively unstable pharmaceutical ingredient is selected from the group consisting of ketotifen, its pharmaceutically acceptable salts and mixtures thereof. 30. The ophthalmic composition according to claim 17, wherein the stabilizing agent is a calcium salt of diethylene triamine pentaacetic acid, an effective amount of said stabilizing agent is from about 100 μmol / L to about 1000 μmol / L, and the oxidatively unstable pharmaceutical ingredient is selected from the group consisting of from ketotifen, pharmaceutically acceptable salts of ketotifen and mixtures thereof. 31. An ophthalmic composition according to claim 17, wherein the pH is from about 6.6 to about 7.2. 32. An ophthalmic composition comprising an oxidatively unstable pharmaceutical ingredient and an effective amount of a stabilizing agent, wherein the stabilizing agent is selected from the group consisting of silica, N, N, N ', N', N '', N '' - hexa (2- pyridyl) -1,3,5-tris (aminomethyl) benzene, diethylene triamine pentaacetic acid, salts of diethylene triamine penta acetic acid and acid, wherein the pH is from about 6.8 to about 7.2.

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